Immunology of Idiosyncratic Drug Reactions

Introduction

A reaction to a drug, any other type of adverse reaction, stands out among its counterparts as there can be no correlation due to misclassification of the IDRs about the pharmacology of the drug. Clinical manifestations of such reactions include rashes, hepatitis, and, in critical cases, multi-organ failure. This unpredictability and infrequency of IDRs hinder effective clinical practice both in terms of the safety of patients and the development of products. It is also imperative to provide clinically relevant knowledge of the IDRs to enhance the existing therapeutic strategies.

What Is the Role of Genetic Predisposition in the Development of Idiosyncratic Drug Reactions?

The genetic predisposition to develop certain illnesses is another key aspect when it comes to reactions to drugs. Some individuals also have endogenous genes that act as risk factors and make them prone to atypical adverse reactions. A great deal of genetic variance concerns variations within genes coding for drug-transforming enzymes like the cytochrome P450 family. Mutations in these genes can impair the metabolic breakdown of drugs, leading to accumulation of medicinal reactive intermediates in the body. These reactive intermediates could bind to peptides, cells, and some will activate immune response for instance idiosyncratic drug response that is immunologically mediated.

Another genetic element is the presence of certain human leukocyte antigen HLA, which includes major elements of the immune system. HLA molecules work by mounding abnormal or foreign peptides to T cells and activating them. Several HLA alleles have been found to correlate strongly with severe IDRs, such as Stevens-Johnson’s syndrome, acute generalized exanthematous pustulosis, and toxic epidermal necrolysis. Severe IDRs in individuals containing these alleles mainly occur because their drug-modified proteins are considered dangerous by their active immune systems.

This genetic background explains the observation that some patients exposed to the same drug and are said to be hypersensitive to that drug will only present the reaction in a subset of the population. Therefore, assessing the patient’s genetics would be useful in establishing present or future management strategies that aim to avert more serious reactions. However, progressing with this understanding, currently, drugs are prescribed without the use of genetic tests, though there are glaring efforts to change this in the nearest future.

How Do Drugs or Their Metabolites Trigger an Immune Response in Idiosyncratic Drug Reactions?

In the case of drug-related idiosyncratic reactions, it is common to find that such drugs or their metabolites associate themselves with the proteins in the body and trigger an immune response such that protein modifications may be perceived as foreign. One of the key mechanisms involved in this process is hapten formation. Haptens are low molecules such as drugs or anticancer metabolites, that are not capable of inducing immunogenicity. But, upon the covalent bonding of these molecules to the endogenous proteins drug-protein conjugates are formed which the immune system mounts a response against. This alteration of self-proteins also changes the conformation of bound proteins, which are recognized as non-self antigens to the immune system and are therefore upregulated.

APCs, like dendritic cells, internalize these drug-protein complexes. These APCs degrade these complexes and display the modified peptides via their MHC molecules. T cells are stimulated by TCRs when they detect these altered peptide-MHC complexes. This stimulation can also induce a variety of effector functions, including inflammation, cytotoxic activity, and the recruitment of other effector cells depending on the environment and the subset of the T cell.

On top of the hapten mechanism, drugs can also provoke an immune response via another pathway called the “p-i concept,” or pharmacological interaction with the immune system. Some medications can bind to TCR and other immune receptors without a hapten. Therapeutic agents or their metabolites bidirectionally and reversibly associate with TCRs or MHC complexed peptides and activate T-cells like any other antigen. This is quite unique, there is no requirement for the usual class II-dependent antigen processing and hence, T cells can be activated fairly quickly and the response can even occur without prior sensitization.

What Immune Cells Pathways Are Primarily Involved in Mediating Idiosyncratic Drug Reactions?

The response towards drugs in the case of idiosyncratic drug reactions (IDRs) is a multi-faceted phenomenon with many immune cells and pathways involved, but T cells are the main orchestrators of these reactions. CD4+ and CD8+ T cells, the helper and cytotoxic cells, respectively, are important in the Induction of IDRs, but they do this in different ways that add up to the influence on the immune response.

Recognition of drug-protein conjugates which are expressed by antigen presenting cells using MHC class II is a function that mainly involves CD4+ helper T cells. Upon recognizing such drug-protein conjugates, CD 4+ T cells activate, proliferate and differentiate to subtypes such as Th1, Th2, or Th17 cells by the levels of various cytokines in the tissue. The secreted CD4+ T cells activate the immune system by producing products known as cytokines. For example, Th1 cells, which respond to inflammatory cytokines, produce interferon-gamma and tumor necrosis factor-alpha, which participate in inflammatory responses and activate macrophages. Th2 effector cytokines are IL-4, IL-5 and IL-13, which relate to the recruitment of eosinophils and stimulation of antibody production. This type of inflammation, due to synchronization with other cytokines will cause more immune cells to be recruited and activated which would further aggravate the destruction of respective tissues and lead to the symptoms such as rashes or injury to organs.

The role of CD8+ cytotoxic T cells is more pronounced in damage in IDRs. This approach is based on the premise that these cells can recognize drug-modified peptides that are presented by MHC class I molecules. When activated, CD8+ T cells are capable of engaging and destroying such modified cells using releasing cytotoxic factors such as performance and granzyme. Perforin possesses the key function of forming pores on the membrane of target cells, thereby enabling the entry of granzymes into the cells with the purpose of inducing apoptosis. This kind of activity explains the reason as to why some IDRs are accompanied with severe tissue destruction, for example, toxic epidermal necrolysis where there are massive losses of cells and skin sloughs off.

Apart from T cells, other cells may also be involved in the disease process of IDRs. Other innate immune cells, called natural killer (NK) cells may be activated at the very early stages of the immune response triggered by drug-induced stress or damage. NK cells are capable of destroying abnormal cells even in the absence of MHC Class I molecules on their surface which is very possible due to drug related cellular stress. In addition, NK cells can also enhance the immune response through the secretion of pro-inflammatory cytokines or by contacting other immune cells.

Can Idiosyncratic Drug Reactions Be Prevented?

Idiosyncratic drug reactions (IDRs) are notoriously difficult to predict and even more difficult to prevent. This is because the accordant reactions with irrationality are extremely rare and occur only in certain individuals. Nevertheless, there is some research in this regard, especially in pharmacogenomics in recent years which have provided different approaches in the IDR, for example, in wholly revolving this ID trial, risk profiling individuals at higher risk of IDR and also applying preventive measures.

Targeted genomic screening has proven most useful in this regard. This process involves obtaining the patient's genetic profile and determining the presence of predisposing genetic variants that cause drug idiosyncrasy. Before treatment is initiated, the patients are screened for specific HLA alleles, and their response to treatments with particular drugs can be prevented by clinically-initiated interventions that escalate behaviors or change treatments in response to adverse toxins.

Apart from pharmacogenomics, new technologies have also been established to in vitro assess the idiosyncratic drug reactions potential of a drug. These functional assays involve assessing T lymphocyte activation (or cytokine production) upon exposure to the drug of interest. While these assays are useful in determining the overall immunogenicity of a compound, most of these tests are not practical for everyday clinical practice because of their high cost and complexity, as well as the special laboratory conditions required.

Conclusion

Adverse reactions to pharmacological agents that are unpredictable and occur in certain patients only in a very different manifestation than expected complicate the process of drug therapy in general and interferon therapy in particular. Immunotoxicity of drugs involves heritable features such as metabolism and immune response. We have made progress in understanding these processes, especially in finding the genetic determinants. However, the problem of predicting and preventing individual drug reactions is still critical.